EP1713459B1 - Use of sphingosine-1-phosphate (s1p) receptor agonists for the treatment of brain degenerative diseases - Google Patents

Use of sphingosine-1-phosphate (s1p) receptor agonists for the treatment of brain degenerative diseases Download PDF

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Publication number
EP1713459B1
EP1713459B1 EP04804037A EP04804037A EP1713459B1 EP 1713459 B1 EP1713459 B1 EP 1713459B1 EP 04804037 A EP04804037 A EP 04804037A EP 04804037 A EP04804037 A EP 04804037A EP 1713459 B1 EP1713459 B1 EP 1713459B1
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Prior art keywords
receptor
treatment
sphingosine
cells
phosphate
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English (en)
French (fr)
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EP1713459A2 (en
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Volker Brinkmann
Nicole Kaneider
Christian J. Wiedermann
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Novartis Pharma GmbH
Novartis AG
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Novartis Pharma GmbH
Novartis AG
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Definitions

  • the present invention relates to a new use for a sphingosine-1-phosphate (S1 P) receptor agonist FTY720 in the treatment of progressive dementia or brain degenerative diseases, selected from the group consisting of Pick's disease or cerebral atherosclerosis.
  • S1 P sphingosine-1-phosphate
  • S1P receptor agonists are compounds which signal as agonists at one or more sphingosine-1 phosphate receptors, e.g. S1P1 to S1P8.
  • Agonist binding to a S1P receptor may e.g. result in dissociation of intracellular heterotrimeric G-proteins into G ⁇ -GTP and G ⁇ -GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling pathways/kinases, or to internalization/desensitization of the receptors as a result of super-agonism and consequently an antagonism of receptor signaling by the natural ligand S1 P.
  • the binding affinity of S1P receptor agonists to individual human S1P receptors may be determined in following assay:
  • S1P receptors Internalization and desensitization of S1P receptors is determined using e.g. Chinese hamster ovary (CHO) cells transfected with a myc-tagged human S1P receptor. Internationalization of the receptor as a results of stimulation by agonists is determined by FACS analysis using fluorescently labeled anti-myc antibodies.
  • CHO Chinese hamster ovary
  • S1P receptor agonists are e.g. compounds which in addition to their S1P binding properties also have accelerating lymphocyte homing properties, e.g. compounds which elicit a lymphopenia resulting from a re-distribution, preferably reversible, of lymphocytes from circulation to secondary lymphatic tissue, without evoking a generalized immunosuppression.
  • Na ⁇ ve cells are sequestered; CD4 and CD8 T-cells and B-cells from the blood are stimulated to migrate into lymph nodes (LN) and Peyer's patches (PP).
  • the lymphocyte homing property may be measured in following Blood Lymphocyte Depletion assay:
  • Examples of pharmaceutically acceptable salts include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine.
  • the compounds and salts of the combination of the present invention encompass hydrate and solvate forms.
  • the S1P receptor agonist used in the present invention is FTY720, i.e. 2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutical acceptable salt form (referred to hereinafter as Compound A), e.g. the hydrochloride, as shown:
  • Brain degenerative diseases are becoming more common in developed countries as the population includes more and more older persons. There is no known cause for the diseases. It is not known why some people present as early as 30 or 40 years of age with dementia while others do not present until their late 70's or 80's.
  • Alzheimer disease is a progressive degenerative disease of the brain characterized by the insidious onset of dementia. Impairment of memory, judgment, attention span, and problem solving skills are followed by global loss of cognitive abilities. There remains a medical need for agents which are effective in the treatment of such diseases and disorders, e.g. in reducing or preventing disease progression and/or alleviating the symptoms and/or improving quality of life.
  • WO03/094965 mentions the use of SP1 agonists, such as peptides, small molecules, antibodies or affibodies, for reducing symptoms of neurological disorders such as neurodegenerative disorders, including e.g. Alzheimer's disease, multi-infarct dementia and Lewy-body dementia.
  • US6004565A describes compounds having accelerated lymphocyte homing immunosuppressive properties, such as 2-aminopropane-1,3-diol compounds and in particular 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, and mentions the use of such compounds in the prevention and Treatment of a long list of diseases, including amyloidosis.
  • EP0812588A mentions external preparation for topical administration containing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol as active ingredient.
  • EP0 8 125 8 8A describes that this compound may be used in the prevention and treatment of a long list of diseases, including amyloidosis.
  • S1 P receptor agonists have interesting properties which make them useful for treating progressive dementia and brain degeneration.
  • S1P sphingosine-1-phosphate
  • Peripheral blood mononuclear cells are prepared from peripheral venous blood of healthy volunteers (anticoagulated with EDTA). After Lymphoprep R density gradient centrifugation, peripheral blood mononuclear cells are collected and washed three times with normal saline. Positive selection of monocytes is performed by adding MACS colloidal superparamagnetic microbeads conjugated with monoclonal anti-human CD14 antibodies to cooled, freshly prepared peripheral blood mononuclear cell preparations in MACS buffer (PBS with 5 mM EDTA and 0.5% bovine serum albumin) according to the manufacturer's instructions. Cells and microbeads are incubated for 15 min at 4-6°C.
  • MACS buffer PBS with 5 mM EDTA and 0.5% bovine serum albumin
  • the separation column is positioned in the MACS magnetic field and washed with MACS buffer at room temperature.
  • the cells are washed with MACS buffer, resuspended, and loaded onto the top of the separation column.
  • the eluent containing CD14 cells is withdrawn and after removal of the column from the magnet, trapped monocytes (CD14*) are eluted with the sixfold amount of cold MACS buffer, centrifuged, and resuspended in medium containing 0.5% BSA.
  • CD14* trapped monocytes
  • Leukocyte migration is measured using a modified 48-blindwell microchemotaxis chamber equipped with 5 ⁇ m pore-sized nitrocellulose filters for monocyte chemotaxis.
  • cells are incubated for 20 min with GFX [500nM], staurosporine [10ng/mL], tyrphostin-23 [10 ng/mL], wortmannin [10 nM], cholera toxin [1 nM], DMS [20 pg/mL to 20 ⁇ g/mL] or pertussis toxin [1 nM].
  • a ⁇ 's potency to affect monocyte chemotaxis toward fMLP cells with A ⁇ [1 aM to 1 ⁇ M] are incubated for 20 min. After washing twice, 50 ⁇ l of cell suspension [1x10 6 cells/mL] is put into the upper compartment of the chemotaxis chamber and cells are allowed to migrate for 90 min toward fMLP. After these migration periods the filters are dehydrated, fixed and stained with haematoxylin-eosin. Migration depth is quantified by microscopy, the distance from the surface of the filter to the leading front of three cells being measured. Data are expressed as "chemotaxis index", which is the ratio between the distance of directed and undirected migration.
  • RNA Total RNA is isolated from 8 ⁇ 10 6 cells by phenol-chloroform-isoamylalcohol extraction (RNACleanTM; Hybaid-AGS, Ulm, Germany).
  • Reverse transcriptase reaction is performed on 1 ⁇ g of RNA using random hexamers reverse transcriptase (Gibco BRL, Life Technologies, Vienna, Austria). 10 ⁇ L of the reverse transcriptase reaction mixture is then subjected to 35 cycles of PCR in a 50 ⁇ L reaction mixture containing 1 pmol of sense and anti-sense primer pairs in a Perkin-Elmer thermocycler: 95°C - 30 sec (denaturation), 53°C - 60 sec (annealing), 72°C - 30 sec (extension).
  • Hot Start Taq polymerase is from Qiagen Inc. (Valencia, CA, USA). Primers (MWG Biotech, Ebersdorf, Germany) are designed to amplify about 400 bp coding sequences of the receptors. Primers are designed as follows: Sphingosine-1-phosphate receptor (S1 PR) 1 sense: CTG TGA ACA ATG CAC TGG, anti-sense: CCT ACG TAC TCA ACA TAG CC. S1PR 3 sense: ATC TGC AGC TTC ATC GTC, anti-sense: AGA TTG AGG CAG TTC.
  • S1 PR 2 sense: ACC ACG CAC AGC ACA TAA TG
  • anti-sense AAA CAG CAA GTT CCA CTC GG.
  • S1 PR 4 sense: TGA ACA TCA CGC TGA GTG
  • anti-sense ATC ATC AGC ACC GTC TTC.
  • S1PR 5 sense: GAA ATG CAG CCA AAG GTG
  • anti-sense TT ATC ACC CAC AAG GTC CTT C.
  • the PCR products are subjected to agarose gel analysis.
  • a ⁇ and A ⁇ precursor protein-induced chemotaxis A ⁇ and A ⁇ precursor protein-induced chemotaxis.
  • monocytes are allowed to migrate toward different concentrations of A ⁇ [10 nmol/L to 1 ⁇ mol/L] or A ⁇ -PP [10 nmol/L to 1 ⁇ mol/L] for 90 min.
  • Directed migration of monocytes is measured using a modified 48-blindwell microchemotaxis chamber equipped with 5 ⁇ m pore-sized nitrocellulose filters for monocyte chemotaxis. Migration depth is quantified by microscopy, measuring the distance from the surface of the filter to the leading front of three cells. Data are expressed as "chemotaxis index", which is the ratio between the distance of directed and undirected migration.
  • neuropeptides e.g. bombesin, CGRP, SP, SN or VIP and chemotaxis toward A ⁇ and A ⁇ -PP is tested as described above. All neuropeptides inhibit chemotaxis concentration-dependently.
  • Monocytes are incubated with several enzyme blockers.
  • the protein kinase C inhibitor GFX, the tyrosine kinase inhibitor tyrphostin-23, and the phospholipase-3 inhibitor WTN are used first for blocking signaling enzymes; involvement of G proteins is then tested with PTX which is known to induce Gi proteins, and CTX which induces Gs proteins.
  • chemotaxis experiments toward A ⁇ (1pmol/l) and A ⁇ -PP (1 pmol/l) are performed. Data are expressed as chemotaxis index, which is the ratio between directed and random migration. Mean distance of random migration is 54 ⁇ 3.2 ⁇ m.
  • N,N-dimethylsphingosine inhibits A ⁇ - and A ⁇ -PP-induced monocyte migration
  • DMS selective sphingosine kinase inhibitor
  • S1P receptor agonist deactivates migration of human monocytes toward A ⁇ and chemokines
  • Monocytes are incubated with DMS, Compound A or medium for 20 min. After washing, chemotaxis experiments toward A ⁇ [1 pmol/L] are performed. Data are expressed as chemotaxis index, which is the ratio between directed and random migration. Mean distance of random migration is 56 ⁇ 5.6 ⁇ m. DMS and a S1P receptor agonist alone inhibit the migration of the cells, whereas co-treatment with both restores the chemotactic effect of A ⁇ and A ⁇ -PP. Results with Compound A are as follows: Table 2 Chemotaxis Treatment Mean (+/- SEM) Medium 1.825 (0.14) DMS (2 ng/ml) 1.423 (0.98) Compound A (2 ng/ml) 1.077 (0.18)
  • S1P receptor mRNA expression is regulated by A ⁇
  • chemotaxis index which is the ratio between directed and undirected migration of cells.
  • RT-PCR is performed and equal amounts of cDNA are subjected to agarose gel electrophoresis. Induction of S1 PR 2 and S1 PR 5 mRNA in A ⁇ -treated cells is observed.
  • S1P receptor agonist Daily dosages required in practicing the present invention when S1P receptor agonist is used will vary depending upon, for example, the compound used, the host, the mode of administration and the severity of the condition to be treated.
  • a preferred daily dosage range is about from 0.1 to 100 mg as a single dose or in divided doses.
  • Suitable daily dosages for patients are on the order of from e.g. 0.1 to 50 mg p.o.
  • the S1P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g. in the form of injectable solutions or suspensions.
  • Suitable unit dosage forms for oral administration comprise from ca. 0.1 to 30 mg, usually 0.25 to 30 mg S1P receptor agonist selected from Compound A, together with one or more pharmaceutically acceptable diluents or carriers therefor.
  • the S1P receptor agonist may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions, or topically.
  • Pharmaceutical compositions comprising a S1P receptor agonist selected from compound A may be manufactured in conventional manner, e.g. as described in EP-A1-627,406 or in EP-A1-1,002,792 .
  • the S1P receptor agonists may be administered as the sole ingredient or together with other drugs useful in the alleviation or treatment of brain degenerative diseases or progressive dementia, e.g. an AMPA receptor agonist, a noortropic agent, a painkiller or an anti-inflammatory agent.
  • other drugs useful in the alleviation or treatment of brain degenerative diseases or progressive dementia e.g. an AMPA receptor agonist, a noortropic agent, a painkiller or an anti-inflammatory agent.
  • AMPA receptor antagonist includes an quinoxaline-dione aminoalkylphosphonate , e.g. as disclosed in WO 98/17672 , or to further compounds such as EGIS 8332 (7-acety)-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carbonitrile), GYKI 47261 4-(7-chloro-2-methyl-4H-3,10,10a-triaza-benzo[f]azulen-9-yl)-phenylamine), irampanel (BIIR 561; N,N-dimethyl-2-[2-(3-phenyl-1,2,4-oxadiazo(-5-yl)phenoxy]ethanamine), KRP 199 (7-[4-[[[[(4-carboxyphenyl)-amino]carbonyl]oxy]methyl
  • YM90K (6-imidazol-1-yl-7-nitro-1,4-dihydro-quinoxaline-2,3-dione), S-34730 (7-chloro-6-sulfamoyl-2-(1H)-quinolinone-3-phosphonic acid), Zonampanel (YM-872; (7-imidazol-1-yl-6-nitro-2,3-diaxo-3,4-dihydro-2H-quinoxalin-1-yl)-acetic acid), GYKI-52466 (4-(8-methyl-9H-1,3-dioxa-6,7-diaza-cyclohepta[f]inden-5-yl)-phenylamine), ZK-200775 (MPQX, (7-morpholin-4-yl-2,3-dioxo-6-trifluoromethyl-3,4-dihydro-2H-quinoxalin-1-ylmethyl)-phosphonic acid), CP-4650
  • nootropical plant extracts includes extracts from Ginkgo leafs.
  • calcium antagonists includes cinnarizine and nimodipine.
  • cholinesterase inhibitors includes donepezil hydrochloride, rivastigmine and galantamine hydrobromide.
  • purine derivates as used herein includes pentifyllin.
  • a painkiller as used hereien includes, ibuprofen.
  • a suitable anti-inflammatory agent is e.g. a NSAIDs, e.g. naproxen.
  • Extracts from Ginkgo leafs can be administered, e.g., in the form as marketed, e.g. under the trademark GinkodilatTM according to the information provided by the package insert.
  • Cinnarizine can be administered, e.g., in the form as marketed, e.g. under the trademark Cinnarizin forte-ratiopharmTM.
  • Nimodipine can be administered, e.g., in the form as marketed, e.g. under the trademark NimotopTM.
  • Donepezil hydrochloride can be administered, e.g., in the form as marketed, e.g. under the trademark AriceptTM.
  • Rivastigmine can be prepared as disclosed in US 5,602,176 .
  • Galantamine hydrobromide can be administered, e.g., in the form as marketed, e.g. under the trademark ReminylTM.
  • Dihydroergotoxin can be administered, e.g., in the form as marketed, e.g, under the trademark HyderginTM.
  • Nicergoline can be administered, e.g., in the form as marketed, e.g. under the trademark SermionTM.
  • Piracetam can be administered, e.g., in the form as marketed, e.g. under the trademark CerebroforteTM.
  • Pentifyllin can be administered, e.g., in the form as marketed, e.g. under the trademark CosaldonTM.
  • Pyritinol can be administered, e.g., in the form as marketed, e.g. under the trademark EncephabolTM.
  • Vinpocetin can be administered, e.g., in the form as marketed, e.g. under the trademark CavintonTM.
  • co-administered compound will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition to be treated, and so forth.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • S1P receptor agonists are well tolerated at dosages required for use in accordance with the present invention.
  • Compound A has an acute LD 50 > 10 mg/kg p.o. in rats and monkeys.

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EP04804037A 2003-12-19 2004-12-17 Use of sphingosine-1-phosphate (s1p) receptor agonists for the treatment of brain degenerative diseases Not-in-force EP1713459B1 (en)

Priority Applications (2)

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PL04804037T PL1713459T3 (pl) 2003-12-19 2004-12-17 Zastosowanie agonistów receptorów sfingozyno-1-fosforanu (S1P) do leczenia chorób zwyrodnieniowych mózgu
EP09177200.4A EP2213285B1 (en) 2003-12-19 2004-12-17 Use of sphingosine-1-phosphate (S1P) receptor agonists in combination with a second agent for the treatment of brain degenerative diseases

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GBGB0329498.0A GB0329498D0 (en) 2003-12-19 2003-12-19 Organic compounds
PCT/EP2004/014436 WO2005058295A2 (en) 2003-12-19 2004-12-17 Use of sphingosine-1-phosphate (s1p) receptor agonists for the treatment of brain degenerative diseases

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GB0329498D0 (en) 2004-01-28
AU2004298760A1 (en) 2005-06-30
KR20120099499A (ko) 2012-09-10
PT1713459E (pt) 2010-09-06
US20130281541A1 (en) 2013-10-24
EP2213285A3 (en) 2010-10-20
US20110124739A1 (en) 2011-05-26
US20080139662A1 (en) 2008-06-12
KR101232934B1 (ko) 2013-02-13
US8519006B2 (en) 2013-08-27
JP2007514698A (ja) 2007-06-07
BRPI0417203A (pt) 2007-02-06
CN101791406B (zh) 2013-08-14
EP2213285B1 (en) 2013-11-06
US20140162964A1 (en) 2014-06-12
AU2004298760B2 (en) 2009-05-21
EP2213285A2 (en) 2010-08-04
CA2792467A1 (en) 2005-06-30
JP5469122B2 (ja) 2014-04-09
ES2348569T3 (es) 2010-12-09
CA2545503A1 (en) 2005-06-30
CN1893934B (zh) 2010-05-26
EP1713459A2 (en) 2006-10-25
KR101342244B1 (ko) 2013-12-16
RU2006125744A (ru) 2008-01-27
PL1713459T3 (pl) 2010-12-31
CN101791406A (zh) 2010-08-04
ATE474569T1 (de) 2010-08-15
CA2545503C (en) 2013-08-20
DE602004028286D1 (de) 2010-09-02
ES2444717T3 (es) 2014-02-26
MXPA06006924A (es) 2006-08-23
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